Unlike the well established thermal Huisgen cycloaddition reaction (Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, p 1-176), the Cu-catalyzed version thereof disclosed in U.S. Pat. No. 7,375,234 to Sharpless et al., offers consistent 1,4-stereoselectivity, is not limited to highly activated alkynes, and proceeds efficiently even at micromolar concentrations of reactants in aqueous media. Many investigators have reported the use of amines as copper-binding ligands and/or protic bases to aid azide-alkyne cycloaddition reactions, including 2,6-lutidine, triethylamine, N,N,N′-trimethylethylenediamine, diisopropylethylamine, proline, AMBERLYST® A21 amine resin, and other aliphatic amines. The most commonly used ligand for copper-catalyzed azide-alkyne cycloadditions has been tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA, 1) discovered by the Sharpless laboratory (Chan, T. R.; et al. Org. Lett. 2004, 6, 2853-2855).
There is an ongoing need for copper ligands to further enhance the rate, efficiency and/or efficacy of the copper-catalyzed azide-alkyne cycloaddition reactions. The present invention fulfills this need.